Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation and differentiation of mononuclear phagocytes and the function of other cells of the female reproductive tract. It is either secreted as a glycoprotein or chondroitin sulfate-containing proteoglycan, both of which are found in biologically active concentrations in the circulation, or expressed in biologically active form at the cell surface as a membrane spanning glycoprotein. The cell surface CSF-1 and the proteoglycan CSF-1 can act in a localized fashion, the former by direct cell-cell interaction with target cells or by local proteolytic release of soluble growth factor from the cell surface, and the proteoglycan CSF-1 by its sequestration to particular extracellular matrices. Studies with the osteopetrotic (csfm-op/csfm-op) mutant mouse, that possesses an inactivating mutation in the CSF-1 gene, indicate that CSF-1 is the primary regulator of mononuclear phagocyte production. They also indicate that CSF-1, via its local and humoral action on target cells, regulates many processes that are vital for the normal development and function of a variety of non-hematopoietic tissues and organs, including bone, brain, dermis and the reproductive organs. In addition, other studies indicate that CSF-1 plays an important autocrine or paracrine role in leukemias and in neoplasias of the female reproductive system. The overall aim of this proposal is to further understand the biological roles of CSF-1 and the CSF-1 receptor (CSF-1R). Answers will be sought to the following questions: 1) Which cell types synthesize CSF-1 in vivo? How is CSF-1 synthesis by these cell types regulated? 3) What forms of CSF-1 (secreted glycoprotein, proteoglycan or cell surface) regulate the various CSF-1 target cells? 4) Are all of the effects of CSF-1 mediated via the known CSF-1R (c-fms protooncogene product)? 5) Is this receptor regulated by other ligands? 6) How is CSF-1 involved in the development of mouse radiation-induced leukemias that exhibit autocrine regulation by CSF-1? The specific aims are: 1.To identify the cells that synthesize CSF-1 in vivo. 2. To elucidate the regulation of CSF-1 gene expression. 3.To determine the mechanism of regulation of the various CSF-1 responsive cells in different tissues and to analyze their functions. 4.To disrupt the mouse CSF-1R gene and analyze the phenotype of CSF-1R-null mice. 5. To elucidate the role of CSF-1 in the development of radiation-induced leukemias of SJL/J mice.
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